All references mentioned throughout this document are explicitly incorporated included herein by reference.
Recently, a novel synthetic route toward hydrophobically modified poly(acrylic acid), which is a hybrid between post-polymerization modification and a free-radical copolymerization, has been discovered [Bromberg, L. A Novel Family of Thermogelling Materials via C—C Bonding Between Poly(acrylic acid) and Poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide), J. Phys. Chem. B 1998, 102, 1956; Bromberg, L. Polyether-modified Poly(acrylic acid): Synthesis and Properties, Ind. Eng. Chem. Res. 1998, 37, 4267]. These references are explicitly incorporated herein by reference. Without intending to be bound by any particular mechanism, it is believed that PAA segments are grafted onto a polyether backbone (typically represented by a PEO-PPO-PEO copolymer) via C—C bonding. It is believed that he PEO-PPO-PEO copolymers act as chain transfer agents in polymerization of acrylic acid, when hydrogen abstraction from these polyethers is allowed. The transfer to propagating polymer in acrylic emulsion polymerization is known to be often substantial and leading to a gelled polymer. The copolymers of PAA and polyethers resulting from the novel synthetic route possess micelle-forming capability and have been used in topical drug delivery, pharmaceuticals, and consumer products [Ron, E. S., Bromberg, L., Luszak, S., Kearney, M., Deaver, D. R., Schiller, M. Smart Hydrogel™: a Novel Mucosal Delivery System, Proc. Intern. Symp. Control. Release Bioact. Mater. 1997, 24, 407; Bromberg, L. E., Mendum, T. H. E., Orkisz, M. J., Ron, E. S., Lupton, E. S. Applications of Poly(oxyethylene-b-oxypropylene-b-oxyethylene)-g-poly(acrylic acid) Polymers (Smart Hydrogel™) in Drug Delivery, Proc. Polym. Mater. Sci. Eng. 1997, 76, 273; Orkisz, M. J., Bromberg, L., Pike, R., Lupton, E. C., Ron, E. S. Polyoxyethylene-b-polyoxypropylene-b-polyoxyethylene-g-poly(acrylic acid) Polymers (Smart Hydrogel™) as a Carrier in Controlled Delivery of Proteins and Peptides, Proc. Polym. Mater. Sci. Eng. 1997, 76, 276; Bromberg, L. E., Orkisz, M. J., Ron, E. S. Bioadhesive Properties of Polyoxyethylene-b-polyoxypropylene-b-polyoxyethylene-g-poly(acrylic acid) Polymers (Smart Hydrogel™), Polym. Prepr. 1997, 38, 626; Bromberg, L. E., Ron, E. S. Protein and Peptide Release from Temperature-Responsive Gels and Thermogelling Polymer Matrices, Adv. Drug Delivery Revs. 1998, 31, 197; Bromberg, L. Self-assembly in Aqueous Solutions of Polyether-modified Poly(acrylic acid), Langmuir 1998, 14, 5806; Bromberg, L. Scaling of Rheological Properties of Hydrogels from Associating Polymers, Macromolecules 1998, 31, 6148; Bromberg, L. Properties of Aqueous Solutions and Gels of Poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide)-g-poly(acrylic acid), J. Phys. Chem. B 1998, 102, 10736; Bromberg, L. E., Goldfeld, M. G. Self-assembly in Aqueous Solutions of Hydrophobically Modified Poly(acrylic acid), Polym. Prepr. 1998, 39, 681; Bromberg, L. Interactions between Hydrophobically Modified Polyelectrolytes and Mucin, Polym. Prepr. 1999, 40, 616; Huibers, P. D. T., Bromberg, L. E., Robinson, B. H., Hatton, T. A. Reversible Gelation in Semidilute Aqueous Solutions of Associative Polymers: a Small-angle Neutron Scattering Study, Macromolecules, 1999, 32, 4889; Bromberg, L. E., Barr, D. P. Aggregation Phenomena in Aqueous Solutions of Hydrophobically Modified Polyelectrolytes. A Probe Solubilization Study, Macromolecules 1999, 32, 3649; Bromberg, L., Salvati, L. Bioactive Surfaces via Immobilization of Self-assembling Polymers Onto Hydrophobic Materials, Bioconjugate Chem. 1999, 10, 678; Bromberg, L., Magner, E. Release of Hydrophobic Compounds From Micellar Solutions of Hydrophobically Modified Polyelectrolytes, Langmuir 1999, 15, 6792; Bromberg, L., Temchenko, M. Loading of Hydrophobic Compounds into Micellar Solutions of Hydrophobically Modified Polyelectrolytes, Langmuir 1999, 15, 8627; Bromberg, L., Temchenko, M., Colby, R. H. Interactions Among Hydrophobically Modified Polyelectrolytes and Surfactants of the Same Charge, Langmuir 2000, 16, 2609, etc.]. These references are explicitly incorporated herein by reference.
These materials are also described in patents and patent applications including L. E. Bromberg, E. C. Lupton, M. E. Schiller, M. J. Timm, G. McKinney, “Responsive Polymer Networks and Methods of their Use”, U.S. Pat. No. 5,939,485, Aug. 17, 1999; L. E. Bromberg, E. C. Lupton Jr., M. E. Schiller, M. J. Timm, G. W. McKinney III, M. Orkisz, B. Hand, “Responsive Polymer Networks and Methods of Their Use”, PCT WO 97/00275, 1997; E. S. Ron, L. Bromberg and M. Temchenko, “End modified thermal responsive hydrogels, U.S. Pat. No. 6,316,011, Nov. 13, 2001; E. S. Ron, L. Bromberg and M. Temchenko,” End modified thermal responsive hydrogels, WO00/07603, Aug. 4, 1999. These references are explicitly incorporated herein by reference.
Specifically noted are these sections from these references. In Bromberg, L. Properties of Aqueous Solutions and Gels of Poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide)-g-poly(acrylic acid), J. Phys. Chem. B.; 1998; 102(52); 10736-10744, p 10738, col 2, line 40 to p 10739 col 1, line 3, (attached), which is included in this specification by reference. “The lower a values measured for all Pluronic-PAA samples to be in the range 0.48<a<0.59 at 15 C, along with the lower intrinsic viscosity to an equivalent molecular weight PAA suggest that the Pluronic-PAA samples possess higher molecular weight per repeat unit. This observation may be interpreted as a regular short-chain branching in Pluronic-PAA and is consistent with the synthetic mechanism, which involves chain transfer.” In Huibers, P. D. T.; Bromberg, L. E.; Robinson, B. H.; Hatton, T. A. Reversible Gelation in Semidilute Aqueous Solutions of Associative Polymers: A Small-Angle Neutron Scattering Study, Macromolecules; 1999; 32(15); 4889-4894, p 4889, col 1, lines 2-12, which was included in this specification by reference. “The polymer formed from grafting the branched polyelectrolyte poly(sodium acrylate) (PAA) to the surface-active triblock copolymer poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO-PPO-PEO) represents a class of unique new materials that undergo reversible gelation in semidilute (1 wt % and below) aqueous solutions over a narrow temperature range. 1-11 The covalent grafting via C—C bonding results in high molecular weight (above 105 Da) PEO-PPO-PEO-g-PAA polymers with regular short-chain branching” and in Huibers et. al Macromolecules, ibid., p 4892, col 2, lines 44-48 “The thermally reversible character of the Pluronic-PAA system can be attributed to its chemical composition and unique block-graft arrangement, resulting in a material with novel physical properties.” The chemical structure of the material is shown in FIG. 3 which is FIG. 5 of Huibers et. al Macromolecules, ibid., p 4893. As FIG. 3 shows, in the “block-graft” structure, the polyacrylic acid chains become bonded onto the polyoxyalkylene molecules, with a carbon from each bonded polyacrylic acid chain replacing a hydrogen on a PEO or PPO moiety. Some polyacrylic acid chains can be bonded to more than one polyoxyalkylene molecule. Note such a multiply bonded PAA-polyoxyalkylene molecule at the lower right of the left hand drawing of FIG. 3.
Previously, the synthesis of such polymers resulted in polymers that were somewhat unstable in conditions of repetitive heating-cooling cycles or under elevated temperature conditions. Unexpectedly, we have discovered that avoidance of the exposure of the polymers to air in the process of their synthesis followed by lyophilization yields usefully stable polymers.